9-aminoalkyl-9-alkyl- or aryl-sulphonyl-fluorenes

ABSTRACT

IN WHICH R1 IS A STRAIGHT OR BRANCHED CHAIN ALIPHATIC RADICAL HAVING 1 TO 6 CARBOM ATOMS, OR A PHENYL OR PTOLYL RADICAL, AND R2 IS A SUBSTITUTED OR UNSATURATED, STRAIGHT OR BRANCHED CHAIN ALIPHATIC RADICAL HAVING 1 TO 5 CARBON ATOMS, WHICH RADICAL MAY CARRY A TERTIARY AMINO RADICAL, SUCH AS A DIALKYLAMINO, MORPHOLINO OR PIPERDINO. THE COMPOUND IS OBTAINED BY REACTING THE CORRESPONDING FLUORENE WITH SODIUM AMIDE AND THEN REACTION THE RESULTING SODIUM DERIVATIVE WITH A HALOGENIDE OF THE FORMULA X-R2, WHEREIN X IS A HALOGEN. THE COMPOUNDS POSSESS DIURETIC AND ANALGESIC PROPERTIES.   9-R2,9-(R1-O2S-)FLUORENE   COMPOUND OF THE FORMULA

United States Patent 3,655,762 9-AMINOALKYL-9-ALKYL- 0R ARYL- SULPHONYL-FLUORENES Jean A. Gautier, Marcel Y. Miocque, Henri Moskowitz,

and Janine L. Blanc-Guenee, Paris, Guy M. Raynaud, Meudon la Foret, and Nicole A. M. Dorme, Paris, France, assignors to Delalande S.A., Courbevoie, Hautsde-Seine, France No Drawing. Filed July 23, 1969, Ser. No. 844,209 Int. Cl. C07c 87/28 US. Cl. 260-570.8 TC 2 Claims ABSTRACT OF THE DISCLOSURE A compound of the formula in which R, is a straight or branched chain aliphatic radical having 1 to 6 carbon atoms, or a phenyl or ptolyl radical, and R is a saturated or unsaturated, straight or branched chain aliphatic radical having 1 to carbon atoms, which radical may carry a tertiary amino radical, such as a dialkylamino, morpholino or piperidino. The compound is obtained by reacting the corresponding fluorene with sodium amide and then reacting the resulting sodium derivative with a halogenide of the formula XR wherein X is a halogen. The compounds possess diuretic and analgesic properties.

The present invention relates to novel derivatives of 9fluorenyl sulphone, their process of preparation and their utilization as medicaments.

The derivatives according to the invention correspond to the general formula:

Rz SOZRI H SOzRi in which R is as defined above, with sodium amide, the

reaction being carried out in an appropirate solvent and,

3,655,762 Patented Apr. 11, 1972 ice in a second stage, reacting the sodium derivative obtained with a halogenide of the general formula:

in which X represents a halogen atom and R is as defined above, the derivative of the general Formula 1 being collected by usual means.

Preferably, the first stage of the reaction is carried out at ambient temperature in toluene or liquid ammonia, taking care in the case where the latter solvent is utilised. to remove it and replace it by toluene in order to proceed with the alkylation, and the second stage is carried out in toluene at the boiling point of the reaction medium for a period of between 3 and 10 hours.

The derivatives of the general Formula 1 so obtained, may be collected, for example, by decantation of the organic phase after cooling and taking up in water and recrystallization in an appropriate solvent.

Certain of the derivatives of the general Formula 2, in particular those in which R represents a butyl radical or a C or C alkyl radical, are novel and have to be synthesised first.

The following preparations are given, by way of example, to illustrate the invention.

EXAMPLE 1 9-diethylaminoethyl-9-butylsulphonylfluorene The following are prepared successively:

(a) 9-butylthio-fluorene; (b) 9-butylsulphonyl-fluorene, and finally (c) 9-diethylaminoethyl-9-butylsulphonyl-fiuorene.

(a) 9-butylthio-fluorene.0.28 mol of butanethiol is added to a solution of 0.25 mol of sodium methylate in 250 ml. of methanol, and the mixture is agitated for 10 minutes at ambient temperature. 0.25 mol of bromofiuorene (in powder form) is then added to the mixture and the suspension is heated for 4 hours at 60-70 C. After cooling, water is added and the mixture is extracted with ether. On evaporation of the etherified phase, a red oil is obtained which is distilled.

Boiling point: 170 C. Viscosity n :1.6170 Yild=50% Empirical formula=C H S Elementary anaZysis.-Calculated (percent): C, 80.16; H, 7.13; S, 16.31. Found (percent): C, 80.29; H, 7.25; S, 12.44.

(b) 9-butylsu1phonyl-fluorene.-0.25 mol of 9-butyl thio-fluorene is dissolved in 150 m1. of glacial acetic acid and heated to -90 C. 150 ml. of volume hydrogen peroxide is then added dropwise thereto over a period of 30 minutes. The reaction is lively and the mixture becomes turbid before the completion of the addition. After cooling, the mixture is poured into iced water. The product is dried and recrystallized in 95 ethanol.

Melting point=102 C. Empirical formula=C H O S Yield=50% Elementary analysis.-Calculated (percent): C, 71.29; H, 6.34, O, 11.17; 8, 11.10. Found (percent): C, 71.44; H, 6.51; O, 11.28; S, 11.00.

(c) 9-diethylaminoethyl-9-butylsulphonyl-fluorene.A suspension of sodium amide (0.1 mol) in ml. of anhydrous toluene is added to 0.1 mol of 9-butylsulphonyl-fluorene. The mixture is progressively heated and maintained under reflux for 3 hours. 0.1 mol of diethylamino chlorethane is then added, and the mixture is kept under reflux for a further 7 hours. After addition of 100 ml. of water, the toluenic phase is decanted and evaporatcd.The residue is recrystallized in isopropyl ether.

Melting point=73 C. Empirical formu1a=C H NO S Yield=52% Elementary analysis.Calculated (percent): C, 71.65; H, 8.10; N, 3.63; O, 8.30; S, 8.32. Found (percent): C, 71.90; H, 8.11; N, 3.38; O, 8.44; S, 8.03.

The compounds listed in the following Table I have been prepared by a similar procedure to that described Melting point: 188 C. Empirical formu1a=C H SO Yield: 67

Elementary analysis.- Calculated (percent): C, 76.72; H, 4.68; O, 9.29; S, 9.31. Found (percent): C, 76.78; H,

above. 4.68; O, 9.26; S, 9.20.

TABLE I R: SO2C4H9 Elementary analysis. percent Yield, M.P., Recrystallization Empirical R2 percent G. solvent formula C H N O S -oHicEoH 75 107 (isoPrhO CzoHmSO: 74-04 3 g 34 -CH1CH N(CH:1)7 38 7s (C Hm0 C21H27NO1S if}? 34;? 3% 41410114444111 6 650F620 0411411046 as tit 74:

84 em OM04 eases: e22 712; as: 7127 i 50 --CH2 CH2 EXAMPLE 2 9-pnopargyl-9-phenylsulphonyl-fiuorcne 0.02 mol of 9-phenylsulphonyl-fluorene in powder form is added to a suspension of 0.02 mol of sodium TABLE II Elementary analysis, percent Yield, M.P., Recrystallization Empirical R7 percent *0. solvent formula C H N O S mm 39 em OM04 {1 31f$f f:::fl:ir2:$ as 277 2:67 CH7cH1N C7H5 7 70 134 (1500111420 CHHWNOZS {821833.81: tilt 3:25 31%? $133 313i --CH:CHzN(iC1H7)z 11s CzH5OH C27Hs1NO2S QZ Y EEE Zia; 3 2g 0 Calculated.... 74. 78 6.52 3.35 7.66 7.68 68 ozHfiOH 95 (MHZYNOS {Found 74. 6.70 3.20 7.57 7.53

Calculate l 71.57 6.01 3.34 11.44 7.64 20 176 CzHaOH CzsHzsNOS GH2CHZN 0 3 {Found 71.42 6.06 3.12 11.64 7.70

CH1CH1OH7N(CH1)7 30 200 CzHsOH 95 C24H25NO2S {gg}g%= 2g g: 3 4 who {testin 727: 2:4: as 21%.; 712

1 Absolute.

TABLE III Elementary analysis, percent Yield, M.P., Recrystallization Empirical R2 percent 0. solvent formula C H N O S OH1CECH 56 204 02115011 CzaHraSOz 3; 2 3g 3: g g; CHzCHzN(CHa)2 70 146 oinmo CziHzaNOg-S 2f; gig CHzCH2N(CzHs)2 60 120 (0411010 Cit-W013 iii? gIii iii iii; iI i cases: @2132 1:2 2:5? n2 n2 Calculated 75.14 6.77 3.25 7.41 7.43 71 161 (0411020 C27HzgNO2S CH2CHZN {Found 75.06 6.85 2.96 7.51 7.46 Calculated--- 78.02 628 3.23 11.07 7.40 35 161 (C4Ho)20 CzaHnNOzS CHZCHQN/ 5 {Found 71.89 611 3.22 11.10 7.38

m w W {ifiififiiik 32:8; 66 3:32 5:82 1:26

The compounds of the general Formula 1 have been tested on laboratory animals and have been shown to possess diuretic and analgesic properties.

(1) Diuretic properties.-The oral administration of the compounds of Formula 1 together with an excess of an isotonic solution of sodium chloride regularly produces increased diuresis in a group of rats with respect to reference animals receiving only the excess of an iso- 40 tonic solution of sodium chloride.

By way of example, the results obtained with certain of the compounds of the general Formula 1 are given in (lilo no 1 This augmentation concerns only the elimination of water, Cland Na+ ions. as K ions remains practlcally unchanged.

(2) Analgesic properties.-The oral administration of the compounds of Formula 1 to mice reduces the number of painful stretchings provoked by the intraperitoneal injection of a solution of acetic acid.

By way of example, the results obtained with two of the compounds of Formula 1 are given in the following Table V.

Considering the results shown in the following Table VI and those shown in the preceding Tables IV and V, the difference between the lethal dose and the pharmacologically active dose of the compounds of Formula 1 is The derivatives of 9-fluorenyl sulphone may be employed in the treatment of the oedema, the hydrosodic retention particularly observed in cases of cardiac and hepatic deficiencies as well as in nephrotic syndromes. They are equally effective in the symptomatic treatment of various algias.

They may be administered in the form of tablets containing 10 to 250 mg. of active ingredient.

What we claim is:

1. A compound according to claim 2, in which R is phenyl and R is -(|1H-CH2N(CH3):

2. A compound of the formula Ra S02R1 wherein R is butyl, phenyl or p-tolyl, and R is dimethylaminoethyl, diethylaminoethyl, dipropylsufiiciently large to permit the use of the aforesaid comaminoethyl, diisopropylaminoethyl, dimethylaminopounds in therapeutics. propyl or dimethylaminoisopropyl.

TABLE VI Dose Percentage administered mortality, R; R: to mice percent 2 Gum oHz0H,1- g/kg/p o 0 H- E CH3 0 a O OH zglkslp 0 CH .k. C S a 15g] g/po -CH:-CH:N\

--CHaOH:m 0

CH: CH: 500 mg./kg./p.o. 50

-GHCH:-N\

References Cited UNITED STATES PATENTS 3,325,544 6/1967 Mofiett 260-570.8

OTHER REFERENCES Burger, Medicinal Chemistry, 2nd ed., pp. 82-83 ROBERT V. HINES, Primary Examiner US. Cl. X.R.

260247.l, 293.4 C, 293.4 D, 293.4 G, 607 B, 609 R; 

